tbuckley/cabot-search huggingface dataset:
Abstract 12308: Presenilin-2 Regulates Mitophagy via Promoting Intracellular Translocation of Parkin to Mitochondria
Authors: Tsunenori Saito, Eitaro Kodani, Roberta A Gottlieb
Journal: Circulation (2022)

Introduction: Presenilin-2 (PS2) is a component of the γ-secretase complex, intracellular protease. Variant in PSEN2 , the causative genes of Alzheimer's disease, are also implicated in the development of dilated cardiomyopathy. Hypoxia increases PSEN2 expression 10-fold over normal, and PSEN2 knockout (PS2KO) cells exhibit significantly lower ATP production. However, the mechanism of the mitochondrial dysfunction has not been fully elucidated. Hypothesis: PS2 regulates mitochondrial selective autophagy (mitophagy) by promoting the translocation of Parkin to mitochondria. Methods: Expression of autophagy and mitophagy markers was examined using cultured rat cardiomyocytes (H9c2) silenced for PSEN2 and PSEN1 , exposed to 10 μM carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial uncoupler used to induce mitophagy. Results: Mitochondrial respiration of PS2KO-H9c2 was showed reduced (maximal respiration capacity, 68.4 ± 27.0 pmol/min/cells) compared to PS1KO-H9c2 (147.6 ± 27.2 pmol/min/cells) or normal cells (276.6 ± 11.9 pmol/min/cells) (P&lt;0.001). When mitophagy-dye modified with perylene-3,4-dicarboxylic anhydride was used, mitophagy detection rates were significantly increased by the addition of FCCP to normal H9c2 (34% increased, P=0.041) and PS1KO-H9c2 (46% increased, P=0.035), but there was no change with PS2KO-H9c2 (25% decreased, P=0.232). When FCCP was added to PS2KO-H9c2, Parkin was not only enhanced in whole cell lysate of PS2KO-H9c2, but also increased even at mRNA level; however, in the isolated mitochondrial fraction, Parkin was significantly reduced, and PINK1 and phosphorylated ubiquitin (serine 65) were also attenuated. In Immunofluorescent staining confirmed that Parkin was not co-localized with mitochondria in PS2KO-H9c2, implicating PS2 in promoting the transfer of Parkin from the cytoplasm to mitochondria. As mitochondrial depolarization causes PINK1 stabilization needed for Parkin recruitment, we interrogated mitochondrial membrane potential measurement using Rhodamine-123 and examined expression of OPA1 isoforms; no significant results were obtained. Conclusions: PS2 contributes to the intracellular transport of Parkin to regulate mitophagy.
Abstract 12005: Association of Prehospital Hypotension Depth and Dose With Survival Following Out-of-Hospital Cardiac Arrest
Authors: Tanner Smida, James J Menegazzi, LEONARD WEISS, Remle Crowe, David D Salcido
Journal: Circulation (2022)

Introduction: Hypotension following resuscitation from out-of-hospital cardiac arrest (OHCA) may cause harm by exacerbating secondary brain injury; however, limited research has explored this relationship. Our objective was to examine the association between duration and depth of prehospital post return of spontaneous circulation (ROSC) hypotension and survival. Hypothesis: We hypothesized that increased severity and duration of post-ROSC hypotension in the prehospital setting would be associated with unfavorable patient outcomes. Methods: We utilized the 2019 and 2020 ESO Data Collaborative public use research data sets for this study (ESO, Austin, TX). Hypotension dose (mmHg*min.), average prehospital systolic blood pressure (SBP), and lowest recorded prehospital SBP were calculated. The association of these measures with survival to home (STH) and rearrest were explored using multivariable logistic regression. Time to hypotension resolution analyses were conducted using Cox proportional hazards models adjusted for known prognostic factors according to the Utstein template. We also assessed the association of hypotension management strategy (push dose vasopressors, vasopressor infusion, or fluid only) with survival, rearrest, and time to hypotension resolution. Results: 17,280 OHCA patients met inclusion criteria, of which 3,345 had associated hospital outcome data. Over one-third (37.8%; 6,526/17,280) of all patients had at least one recorded SBP below 90 mmHg. When modeled continuously, average prehospital SBP (1.19 [1.15, 1.23] per 10 mmHg), lowest prehospital SBP (1.20 [1.17, 1.24] per 10 mmHg), and hypotension dose (0.995 [0.993, 0.996] per mmHg*min.) were independently correlated with STH. Differences in hypotension management were not associated with differences in survival, rearrest, or time to hypotension resolution. Conclusion: Severity and duration of hypotension were significantly associated with poorer outcomes in this dataset. The incidence of hypotension was significantly associated with known unfavorable prognostic factors. Defining a threshold for hypotension requiring treatment above the classical SBP threshold of 90 mmHg may be warranted in the setting of prehospital post-resuscitation care.
Abstract 12457: Usefulness of Automatic Assessment for Longitudinal Strain to Diagnose Wild-Type Transthyretin Amyloid Cardiomyopathy
Authors: Hiroki Usuku, Eiichiro Yamamoto, Tomohiro Fujisaki, Koichi Egashira, Fumi Oike, Koichiro Fujisue, Daisuke Sueta, Seiji Takashio, Kenichi Tsujita
Journal: Circulation (2022)

Introduction: Despite obvious diagnostic usefulness, left ventricular (LV) apical sparing has not been widely accepted to diagnose transthyretin amyloid cardiomyopathy, because it is time consuming and requires a level of expertise. Automatic assessment may be the solution for these problems. Methods and Results: We enrolled 69 patients aged ≥ 70 years who underwent 99m TC-PYP scintigraphy and transthoracic echocardiography (TTE) by EPIQ7G, and had enough information for two-dimensional speckle tracking echocardiography at Kumamoto University Hospital from January 2016 to December 2019. LV apical sparing was diagnosed as relative apical longitudinal strain (LS) index (RapLSI) &gt;1.0. Measurement of LS was repeated using the same apical images with three different measurement packages as follows: (1) full-automatic assessment, (2) semi-automatic assessment, and (3) manual assessment. The calculation time for full-automatically assessment (14.8±1.5 sec/patient) and semi-automatically assessment (67.3±14.1 sec/patient) were significantly shorter than for manual assessment (211.1±60.5 sec/patient) (p&lt;0.01 for both). Receiver operating characteristic curve analysis showed that the area under curve (AUC) of the RapLSI evaluated by full-automatically assessment for 99m Tc-PYP scintigraphy positivity was 0.656 (best cut-off point; 1.12 [sensitivity 63%, specificity 68%]), by semi-automatic assessment was 0.806 (best cut-off point; 1.00 [sensitivity, 61%; specificity, 100%]) and by manual assessment was 0.806 (best cut-off point; 1.00 [sensitivity, 71%; specificity, 96%]). Conclusion: The diagnostic accuracy of semi-automatically assessed RapLSI to predict 99m Tc-PYP scintigraphy positivity was as same as that of manual assessed RapLSI. Semi-automatically approach using novel automated software was useful to diagnose ATTR-CM in the terms of rapidity, reproducibility and diagnostic accuracy.
Abstract 11777: The Prognostic Impact of Living Alone on Long-Term Cardiac Mortality in Patients With Chronic Coronary Syndrome After Percutaneous Coronary Intervention
Authors: Yuta Kurosawa, Akihiko Sato, Takeshi Shimizu, Yuya Sakuma, Himika Ohara, Yuki Muto, Yu Sato, Takatoyo Kiko, Tomofumi Misaka, Akiomi Yoshihisa, Takayoshi Yamaki, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2022)

Background: It has been reported that social frailty is associated with increased mortality in elderly patients with heart failure. However, the prognostic impact of social frailty on mortality in ischemic heart disease is unclear. Here we examined the relationship between living alone, which is one of the criteria for social frailty, and long-term mortality in patients with chronic coronary syndrome (CCS) who underwent percutaneous coronary intervention (PCI). Methods and Results: Consecutive 830 patients with CCS who underwent PCI were enrolled. Patients were divided into two groups according to whether they lived alone or not at the time of discharge. We compared clinical characteristics between two groups and followed cardiac mortality. Patients living alone were younger (66.3 vs. 69.9 years, P = 0.002). The prevalence of comorbidities such as hypertension, diabetes, dyslipidemia, chronic kidney disease, anemia, atrial fibrillation, heart failure, stroke and peripheral artery disease were comparable between two groups. In addition, the rates of medications such as beta-blockers, renin-angiotensin-aldosterone system inhibitors, statins and anti-thrombotic agents did not differ between two groups. In the Kaplan-Meier analysis (mean follow-up period of 1703.9 days), cardiac mortality was significantly higher in the group of patients who were living alone than those who were not (P = 0.008). In the multivariable Cox proportional hazard analyses after adjusting for confounding factors, living alone was an independent predictor of cardiac mortality (hazard ratio 2.44, 95% confidence interval 1.25 - 4.74, P = 0.009). Subgroup analysis which was performed adjusting for interactions between living alone and clinically important variables revealed no interactions. Conclusion: Among CCS patients who underwent PCI, living alone was associated with long-term cardiac mortality regardless of other comorbidities and medications.
Abstract 11289: Suppression of <i>De Novo</i> Purine Synthesis Reduces Development and Progression of Pulmonary Hypertension in Rodent Models
Authors: Qian Ma, Qiuhua Yang, Jiean Xu, Zsuzsanna Bordan, Scott A Barman, David Fulton, Yunchao Su, Yuqing Huo
Journal: Circulation (2022)

Aims: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of pulmonary hypertension (PH). Proliferative cells utilize purine bases from the de novo purine synthesis (DNPS) pathways for nucleotide synthesis, however, it is unclear whether DNPS plays a critical role in VSMC proliferation during development of PH. The last two steps of DNPS are catalyzed by the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC). We investigated whether ATIC-driven DNPS affects the proliferation of pulmonary artery smooth muscle cells (PASMCs) and the development of PH. Methods and Results: Metabolites of DNPS in proliferative PASMCs were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). ATIC mRNA and protein expression was assessed in platelet-derived growth factor (PDGF)-treated PASMCs and in the lungs of PH rodents and patients with pulmonary artery hypertension (PAH). Mice with global and VSMC-specific knockout of Atic were utilized to investigate the role of ATIC in hypoxia-induced PH. ATIC-mediated DNPS at the mRNA, protein and enzymatic activity levels were increased in PDGF-treated PASMCs or PASMCs from PH rodents and patients with PAH. In cultured PASMCs, ATIC knockdown decreased DNPB, nucleic acid DNA/RNA synthesis and reduced cell proliferation. Global or VSMC-specific knockout of Atic attenuated vascular remodeling and inhibited the development and progression of hypoxia-induced PH in mice. Conclusion: Targeting ATIC-mediated DNPS compromises the availability of purine nucleotides for incorporation into DNA/RNA, reducing PASMC proliferation and pulmonary vascular remodeling and ameliorating the development and progression of PH.
Abstract 10858: Mesenchymal Stromal Cell Delivery via Cardiopulmonary Bypass Provides Neuroprotection in a Juvenile Porcine Surgical Model
Authors: Kei Kobayashi, Kamil Sarkislali, Nemanja Saric, Takuya Maeda, Fahad A Somaa, Ankush Bansal, Shao Ching Tu, Mobolanle A Ayodeji, Camille Leonetti, Chao-hsiung Hsu, Jingang Li, Pranav Vyas, Yuka Imamura Kawasawa, Tsang-Wei Tu, Paul C Wang, Patrick J Hanley, Kazue Hashimoto-Torii, joseph A frank, Richard Jonas, Nobuyuki Ishibashi
Journal: Circulation (2022)

Background: Neurodevelopmental impairment is one the most important challenges in children with congenital heart disease. Cardiopulmonary bypass (CPB) causes substantial oxidative/inflammatory stress and microglial activation. The present study tested CPB itself as a unique delivery system of bone marrow-derived mesenchymal stromal cells (BM-MSCs), known to possess significant immunomodulatory properties. Methods: Two-week old piglets were randomly assigned to one of three groups: Control, CPB, and CPB with BM-MSC administration. BM-MSCs (10x10 6 /kg) were delivered through CPB. In addition to cellular/molecular assays, structural and behavioral changes were assessed up to 4 weeks after surgery. Results: Intra-arterial delivery through CPB uniformly distributed BM-MSCs to most of the organs analyzed, including the brain, heart and kidney. In the brain, BM-MSCs were equally distributed between two hemispheres and within the cortex and white matter. While approximately half of the BM-MSCs were localized to parenchyma shortly after CPB, there were no residual MSCs at 4 weeks post-CPB. In the developing cortex, enhanced p53 and JAK-STAT3 pathway activation were revealed post-CPB. BM-MSCs suppressed CPB-induced microglial STAT3 phosphorylation, thereby inhibiting microglial activation. In addition to an increase in anti-inflammatory cytokines, BM-MSCs reduced caspase-3 activation in cortical neurons and limited the induction of apoptotic signals. BM-MSC-treated animals demonstrated improved post-operative recovery and reduced behavioral impairments due to cardiac surgery. Concurrently, CPB-induced structural alterations of the developing cortex were mitigated possibly through the inhibition of prolonged microglia activation by BM-MSCs. No evidence of any detrimental effects was observed. Our transcriptomic analyses suggest that BM-MSC exosome-derived micro-RNA, miR-21-5p, may be the key mediator of apoptosis suppression and reduced microglial activation. Conclusions: BM-MSC delivery via CPB minimizes inflammatory/oxidative stress and reduces neuronal caspase and microglial activation, with subsequent rescue of behavioral/structural impairments in children undergoing cardiac surgery.
Abstract 12352: Left Ventricular Chordal Aberrancy: The Case of a Friend Turned Foe
Authors: Aanchal Sawhney, Jonathan Finkel
Journal: Circulation (2022)

Introduction: Aberrant cardiac structures reported on echocardiography include aberrant papillary muscles, accessory chordae tendineae, ventricular bands, and accessory mitral valve tissue. These usually present with conduction abnormality, obstruction, and heart failure. We report a diagnostic dilemma with a structurally anomalous chord noted on the echocardiogram presenting as recurrent stroke. Case: A 70 year old man presented with complaints of left facial droop, confusion and slurred speech, currently on aspirin and clopidogrel. CT head and MRI brain revealed right middle cerebral artery occlusion and acute on chronic infarcts in multiple vascular territories. Past medical history of recurrent strokes involving the right frontal, occipital lobes, and thalamus suggested embolic aetiology. Transthoracic and Transesophageal Echocardiographic (TEE) examination revealed an anomalous redundant chordal tissue attached to the papillary muscle with no distal attachment, normal mitral valve function without left ventricular outflow tract obstruction. This anomalous chord was present on TEE done 1 year prior but not well visualised at that time. Differentials included ruptured aberrant ventricular band, ruptured chordae tendineae, ruptured papillary muscle with a thrombus or vegetation formation. Due to the chronicity of the condition and negative blood cultures, vegetation was less likely. Recurrent mural thrombus associated with the aberrant chord was identified as the culprit and patient was started on anticoagulation to prevent stroke. Results: All of the aberrant structures reported in current literature have been characterized based on their distal attachment. We excluded accessory papillary muscle and chordae tendineae from the list of differentials as its rupture presents as mitral regurgitation and acute heart failure. The most plausible explanation includes a ruptured false tendon serving as a nidus for thrombus formation with no prior echocardiographic evidence of distal attachment of the fibrous chord. Conclusions: Our case illustrates a very rare entity of an idiopathic primary rupture of a left ventricle false tendon serving as a nidus for clot formation leading to recurrent stroke warranting anticoagulation.
Abstract 12316: Association of State Medicaid Expansion With Incidence of Gestational Diabetes Mellitus Among Nulliparous Individuals in the US, 2012-2019
Authors: Ian Everitt, Kartik Venkatesh, Katharine Harrington, Mercedes R Carnethon, Matthew OBrien, William GROBMAN, Lindsay Pool, Sadiya S Khan
Journal: Circulation (2022)

Introduction: The frequency of GDM and pregnancy-related complications of GDM are increasing in the United States. Detection and treatment are important to manage GDM and reduce the risk of pregnancy-related complications. The objective of this analysis was to assess whether expanding Medicaid, a state-level policy change that enhances access to care, was associated with changes in rates of GDM and outcomes among those with GDM. Methods: Data from nulliparous individuals aged 20-44 years with a first live birth from 30 states between 2012-2019 were included from the National Center for Health Statistics. The primary outcome, age-standardized incidence of GDM, was compared between Medicaid expansion states (N=16) and Medicaid non-expansion states (N=14) using a quasi-experimental analysis with difference-in-differences (DID) models. DID models utilized multivariate linear regression with random intercepts for state (to adjust for unobserved state-level fixed effects), fixed effect for year, and adjustment for state-level covariates including demographics, and health and economic indicators. Secondary outcomes included GDM complicated by preterm birth (≤36 weeks) and high (&gt;4000 grams) or low (&lt;2500 grams) birthweight infants. Results: Among 7,502,838 individuals, age-standardized rates of GDM increased in both Medicaid expansion (49.3 to 56.8 per 1000 births) and non-expansion states (48.6 to 52.7 per 1000 births). Expansion status was associated with a greater increase in rates of GDM (DID +4.32 [95% CI, +1.73 to +6.92] per 1000 births; Figure). Among individuals with GDM, rates of having a preterm birth or a high or low birthweight infant were not significantly different in expansion relative to nonexpansion states. Conclusions: Between 2012-2019, states that expanded Medicaid had a significantly greater increase in incidence of GDM. However, among those with GDM, rates of preterm birth and high or low birthweight did not differ by expansion status.
Abstract 12257: Prognostic Value of Liver T1 Mapping and Extracellular Volume in Dilated Cardiomyopathy
Authors: Jiaqi Wang, Yuanwei Xu, Jiajun Guo, Yangjie Li, Yucheng Chen
Journal: Circulation (2022)

Introduction: Cardiac dysfunction closely correlates with liver congestion and effect on liver relaxation time. Liver relaxometry could provide potential prognostic improvement for dilated cardiomyopathy (DCM) patients. Hypothesis: Liver relaxometry might have prognostic significance for DCM patients. Methods: We prospectively enrolled 433 patients diagnosed with DCM. Cardiac and hepatic T1, T2, and extracellular volume (ECV) were measured on the mid-ventricular mappings. The primary endpoint was defined as heart failure death, sudden cardiac death, and heart transplantation. Results: DCM patients who reached primary endpoint showed significantly increased liver native T1 (770.5±103.2ms versus 813.8±137.0ms, p=0.014) and ECV values (30.9±6.8% versus 34.3±10.7%, p=0.009) and decreased liver T2 value (35.8±5.5 versus 34.1±6.2ms, p=0.038). Right ventricular ejection fraction correlated moderately but significantly with liver native T1 (r =-0.293) and ECV (r=-0.245) (both p&lt;0.001). During the follow-up period (median duration 3.9 years) 97 patients reached the primary endpoint. In the Kaplan-Meier survival analysis, DCM patients with elevated liver native T1 or ECV had higher risk of reaching the primary endpoint (cutoff value: 854.9ms, p=0.001 and cutoff value: 34.5%, p&lt;0.001, respectively). Cox analysis indicated that liver ECV was an independent prognostic factor (hazard ratio:1.042, p&lt;0.001) and showed incremental prognostic value to age, sex, NYHA class III-IV, and LVEF. Conclusions: Liver native T1 and ECV correlates with cardiac magnetic resonance parameters. Furthermore, Liver ECV provides incremental prognostic value in DCM patients.
Abstract 12361: Efficacy and Safety of NOACs vs. Warfarin Across the Continuous Range of Body Mass Index and Body Weight: Insights From COMBINE-AF
Authors: Siddharth M Patel, Jan Steffel, Giuseppe Boriani, Michael G Palazzolo, Erin A Bohula, Anthony Carnicelli, Stuart J Connolly, John W Eikelboom, Baris Gencer, Christopher B Granger, David A Morrow, Manesh R Patel, Lars C Wallentin, Christian T Ruff, Robert P Giugliano
Journal: Circulation (2022)

Introduction: The efficacy and safety of non-vitamin K oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) at the extremes of body mass index (BMI) and body weight (BW) remains uncertain, leading to concerns regarding use in these populations across clinical practice guidelines. Methods: This analysis of the COMBINE-AF database pools individual patient-level data from the 4 pivotal RCTs of NOAC vs. warfarin in AF: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48. Pts randomized to low-dose NOACs not globally approved for clinical use were excluded. The primary efficacy and safety outcome was stroke/systemic embolic event (S/SEE) and major bleeding, respectively, with intracranial hemorrhage (ICH) being a secondary outcome. Outcomes were assessed across BMI and BW using a Cox model stratified by trial, with interaction testing for NOAC vs. warfarin. Restricted cubic splines were used to display the hazard ratio of NOAC vs. warfarin for each outcome across BMI. Results: For 58,464 pts, the median BMI was 28 (25 th -75 th %ile: 25-32) kg/m 2 , with the top 5% (n=2,924) having a BMI ≥ 40 kg/m 2 . For patients randomized to warfarin, the risk of each outcome was lower with increasing BMI (HR per 5 kg/m 2 increase: S/SEE 0.79 [95% CI 0.75-0.84]; major bleeding 0.91 [95% CI 0.87-0.95]; ICH 0.72 [95% CI 0.66-0.80]; p&lt;0.01 for each). There was no significant treatment interaction for NOAC vs. warfarin by BMI for S/SEE (p-interaction = 0.71; Fig 1A ), major bleeding (p-interaction = 0.15; Fig 1B ), or ICH (p-interaction = 0.84; Fig 1C ), such that there was consistent reduction in S/SEE and ICH ( Fig 1A and 1C, respectively ) across the range of BMI with NOAC vs. warfarin. Similar results were seen for each outcome when assessed by BW (median [25 th -75 th %ile]: 81 [70-94] kg; 5 th -95 th %ile: 55-119 kg). Conclusions: In this pooled analysis of the pivotal AF trials, use of NOAC was associated with a consistent reduction in S/SEE and ICH compared with warfarin across the range of BMI and BW.